Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the US and in more than a million veterans over the age of 45, resulting in a tremendous burden of care. The objective of this proposed project is to investigate the role of retinal macrophages and relationship to functional and structural biomarkers of disease progression in dry age-related macular degeneration (AMD), the most common form of AMD (85%) and currently without cures. Development of retinal imaging and blood-based biomarkers to identify individuals with HRD who will progress to NVAMD and GA is important, as these are required to design clinical trials of novel AMD therapies that will benefit the VA population. Our established team combines expertise in retinal ophthalmology and physiology, immunology, pathology, bioengineering and biostatistics, with a track record of studying the pathobiology and the various classes of biomarkers of AMD. Our hypothesis is that infiltration of CD163+ macrophages into the outer retina in patients with intermediate dry AMD will correlate with synaptic defects, possibly explaining the loss of visual function in these patients. We will assess whether infiltrating subretinal macrophages may be associated or may themselves represent the spectral domain optical coherence tomography (SD-OCT) biomarkers of disease progression, specifically reticular pseudodrusen and hyper-reflective foci. We will also evaluate whether high frequency of peripheral blood CD163+ monocytes will correlate with visual dysfunction and retinal imaging biomarkers, suggesting that retinal CD163+ macrophages are derived from recruited circulating CD163+ monocytes. In SA1, using histopathological analysis of postmortem eyes with intermediate AMD with high risk drusen, we will demonstrate that high frequency of outer retinal and subretinal macrophages is associated with markers of retinal damage (especially disrupted photoreceptor synapses) as compared to age-matched control eyes and with imaging markers of reticular pseudodrusen. In SA2, using analysis of circulating monocytes by flow cytometry in subjects with dry AMD, we will show that high expression of peripheral blood CD163+ monocytes in intermediate dry AMD patients will correlate with the presence of SD-OCT markers of disease progression and visual function deficits on psychophysical tests. In SA3, we will also isolate monocytes from blood and postmortem retina, perform analyses of gene expression and released cytokines known to mediate synaptic dysfunction and neurotoxicity with the goal to identify factors that may contribute to loss of vision. This body of work will generate important new knowledge about the role of CD163+ macrophages in AMD patients with high-risk drusen. Our results will be able to show that infiltrating macrophages are the structural correlates of imaging biomarkers of disease progression in eyes with the intermediate form of the disease. This research will enable functional characterization of peripheral monocyte subpopulations to uncover their potential role in pathogenesis and progression of AMD. Importantly, this work will aid in the development of novel endpoints for clinical trials, identification of biomarkers of disease progression and therapeutic targets that will change the standard of care for elderly veterans affected by AMD.